PROJECT SUMMARY/ABSTRACT Adolescence is a critical developmental period during which many psychiatric symptoms first emerge. It has been argued that common alterations within the reward circuitry underlie the development of adolescent-onset psychiatric conditions. Addressing a critical need for the identification of biomarkers early in the course of psychopathologies, this RDoC project examines the neuroimmunology of specific reward processes in adolescents. Specifically, we focus on the clinical phenomenology of anhedonia, a salient feature across psychiatric conditions that often presents as a prodromal psychiatric symptom. However, anhedonia represents a final clinical outcome of several distinct PVS deficits. Therefore, this project examines Reward Expectancy (RE) versus Initial Responsiveness to Reward Attainment (IRRA), reflecting reward anticipation and receipt. This research investigates a novel theory hypothesizing that peripheral inflammation and associated striatal metabolic changes induce specific alterations in the reward circuitry that clinically manifest as anhedonia. We have studied the neuroimmunology and neuronal circuitry of anhedonia and found positive associations between peripheral activity of the kynurenine pathway (KP)-a central neuroimmunological pathway-and anhedonia severity in adolescents. Using MR spectroscopy (1H MRS), we documented associations between blood KP neurotoxins and striatal choline (biomarker for lipid peroxidation) in anhedonic adolescents along with inverse relationships between brain glutathione (antioxidant) and anhedonia severity in adults. Using fMRI, we mapped and identified distinct striatal-based intrinsic functional connectivity (iFC) associated with anhedonia. Additionally, we developed the reward flanker task (RFT) that distinguishes between RE and IRRA. Building upon these compelling preliminary data, we propose a multimodal study to examine the neuroimmunology of specific PVS deficits. We will study 100 psychotropic-free adolescents with diverse psychiatric symptomology (NOS, or full syndromes) and 30 healthy controls group-matched, ages 12-18, Tanner e 4. The study will consist of comprehensive, systematic diagnostic procedures that include dimensional assessments of anhedonia, negative affect, fatigue, and sleep. Peripheral inflammatory measures will include KP activity along with activation status of innate and adaptive immune compartments and responses to both psychological and biological stresses. HPA axis will be indexed by saliva cortisol levels. CNS inflammation will be probed by 1H MRS by measuring chemicals reflecting oxidative stress, lipid peroxidation and mitochondrial function in the striatum, a key region within the reward circuitry. Specific reward processes will be studied using the RFT and striatal based iFC. PUBLIC HEALTH RELEVANCE: The proposed RDoC project is the first to systematically investigate complex immunological processes underlying specific PVS deficits while bringing together a stellar multidisciplinary team of experts. This high-impact translational study targets a critical developmental period and has the potential to elucidate biomarkers early on and to facilitate the development of preventive therapies.